Prostaglandins are well-known active ingredients administered topically to humans or animals in the form of eye drops for the treatment of glaucoma. The usual dosage of these formulas is 1 drop a day in each eye, it being understood that prostaglandins can also be used in combination with a second antiglaucoma agent such as, for example, beta blockers, carbonic anhydrase inhibitors or alpha-adrenergic agonists.
The first disadvantage of prostaglandins is that they are not water-soluble, meaning that they require a solubilization step before including them in the eye drop solution.
Furthermore, another constraint for the formulator is to propose an ophthalmic solution that is chemically stable over time at ambient temperature, in practice over a period of 18 to 24 months. Another characteristic required of the ophthalmic solution is that it should remain stable in relation to the packaging in which it is stored, notably plastic packaging such as low-density polyethylene (LDPE).
One last constraint that can arise is avoiding contamination of the ophthalmic solution by antimicrobial agents, notably in multi-dose packaging. This problem can be solved, however, using single-dose unit packaging or a specialized system for this (ABAK® or COMOD® systems, for example).
Thus, to date, most prostaglandin-based ophthalmic solutions on the market include a preservative which, beyond its antimicrobial properties, also ensures solubilization of the active ingredient and, partially, its stabilization. An example of this is the product sold by Pfizer under the Xalatan® brand, which combines latanoprost and BAK at 0.02% by weight. It should be pointed out that, despite the presence of BAK, these eye drops are not stable at ambient temperature and must be stored cold, at a temperature of approximately 5° C. Furthermore, the Allergan company sells eye drops under the Lumigan® brand, combining bimatoprost and BAK at 0.005% by weight.
However, many publications discourage the use of antimicrobial preservatives, and particularly BAK, for long-term treatments in ophthalmology, as is notably the case of glaucoma, due to tolerance problems (on this subject, see “The New Class of Ophthalmic Agents: Here's how to choose the right prostaglandin for the each patient” by J. James Thimons, O.D., F.A.A.O.—Optometric Management, May 2002).
It thus has now been established that antimicrobial preservatives are toxic in long-term use, to such an extent that today there is a tendency to limit their use by reducing their concentration as much as possible in eye drops or, even better, to eliminate them completely from the formulas.
This problem was taken into account in document WO 97/29752, for example, which discloses the use of a non-ionic agent of the Cremophor® type instead of BAK. In the proposed formula, the BAK concentration is limited to 0.01% by weight, the concentration of Cremophor® EL being 0.05% by weight. A product sold by Alcon, called Travatan®, can be found on the market, combining Travoprost, BAK and Cremophor®.
Polysorbate 80 has also been proposed in ophthalmic solutions to partially reduce the concentration of BAK, as is the case, for example, of the product sold by Novartis under the Rescula® brand, combining unoprostone with a mixture of BAK and polysorbate 80 at 0.015% by weight of the solution.
On the other hand, document US2004/0082660 describes an ophthalmic solution with no BAK and containing a mixture of latanoprost and polysorbate 80.
The problem that the invention proposes to solve is therefore that of developing a prostaglandin-based formula that meets at least the following conditions:                it contains no antimicrobial preservatives;        it is stable over time in a solution at ambient temperature (18 to 24 months, as a minimum);        it is compatible with the plastic packaging in which it is usually stored, notably LDPE packaging;        it is practically as effective in terms of reducing intraocular pressure (IOP) as products available with a BAK base.        
Another objective is to propose a formulation that is sufficiently fluid to be packaged using an aseptic packaging technique such as “Blow-Fill-Seal” (single-dose unit).